Valproic Acid Regulates Gemcitabine-induced Migration And Invasion Of Pancreatic Cancer Cells In A Dose-dependent Manner

ObjectiveCombination chemotherapy is widely used in antitumor regimen because of synergizing effects of drugs.Gemcitabine,as a first-line chemotherapy drug for pancreatic cancer,shows a poor therapeutic effect because of its chemoresistance.Valproic acid(VPA)has been reported to have synergistic anti-tumor effects.This study investigated the effects of different concentrations of VPA in combination with gemcitabine on migration and invasion of pancreatic cancer,and detected the expression of AKT,p38 MAPK,STAT3 and Bmi1 with these treatments,and explored the mechanism of different concentrations of VPA regulating gemcitabine-induced migration and invasion of pancreatic cancer cells.MethodsRelative cell survivals were determined by MTT assay.Bmi1 and related intracellular signaling molecules expression in pancreatic cancer cell lines were detected by Western blot and immunofluorescence staining.Transwell assay was used to measure the migration and invasion abilities of pancreatic cancer cells.And reactive oxygen species(ROS)levels were calculated by flow cytometry.ResultsLow-dose VPA cannot significantly inhibit cell viability of pancreatic cancer cells with or without gemcitabine,but promote the invasion and migration induced by gemcitabine,which could lead to malignant progression of pancreatic cancer;while high-dose VPA can significantly inhibit the viability,invasion and migration of pancreatic cancer cells,thereby exerting anti-tumor effect.Low-dose VPA actives AKT,which further stimulate STAT3/Bmi1 expression and eventually promote migration and invasion of pancreatic cancer cells induced by gemcitabine.Meanwhile,we found that high-dose VPA stimulates p38 MAPK activation,which suppresses STAT3/Bmi1 expression and the acquired migration and invasion of pancreatic cancer cells by gemcitabine.Moreover,these above biological effects induced by gemcitabine in combination with VPA are ROS dependent.ConclusionsLow-dose VPA in combination with gemcitabine further induces the malignant progression,while high-dose VPA synergistically promotes the antitumor effect.Different concentrations of VPA combined with gemcitabine could target STAT3/Bmi1 to exert its corresponding biological effects on pancreatic cancer cells.